Abstract M cells provide the dominant mechanism for sampling microparticles from the intestinal lumen and so have a major influence on the interaction between the luminal microbiota and mucosal tissues. We have defined at least four distinct lineages of M cells in mucosal tissues, with a strikingly similar apical morphology and function in mucosal immune surveillance. In this proposal we focus on novel M cell phenotypes that are inducible in response to inflammation or microbial toxin. The induction of additional M cells in colon and ileum raises the question of the functional dichotomy of M cells ? a ?Sentinel vs Saboteur? problem ? that will provide new insights into microbial pathogenesis, and new perspectives on the host-pathogen relationship. The role of these inducible M cell populations is at the center of our proposal and overall hypothesis, which is that inflammation/infection ?inducible M cell function shifts the role of M cells in the host-pathogen relationship away from routine surveillance, instead favoring entry and colonization by pathogenic microbes. Three aims are proposed: .(1) TNFR signaling and colonic M cells: In this aim, we will examine the requirements for signaling through TNFR1 vs TNFR2 in M cell induction, and identify cellular interactions that influence mucosal immune surveillance. (2) Mechanisms of M cell endocytosis: We will use transfected cell lines, transgenic reporter models, and super-resolution microscopy to identify the machinery used by induced colonic M cells, cholera toxin-induced villous M cells, and conventional Peyer's patch M cells to dissect the available mechanisms for large particle capture. (3). Toxin induction of villous M cells: In this aim, we will examine the ability of cholera toxin to induce these novel Villous M cells, and explore the unique potential of these cells in bacterial colonization and pathogenesis. These proposed studies will provide useful insights into regulation of mucosal adaptive immunity through regulation of immune surveillance mechanisms.